{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:19:10Z","timestamp":1783419550191,"version":"3.54.6"},"reference-count":30,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Thermal ablation (TA) is an increasingly adopted minimally invasive treatment for benign thyroid nodules. However, TA induces marked histological alterations that may simulate thyroid malignancy, creating significant diagnostic pitfalls for pathologists. The present study expands our previous institutional series and further characterizes the morphologic, immunohistochemical, and molecular features of thermally ablated thyroid nodules in order to refine the differential diagnosis with thyroid carcinoma. Fourteen surgically excised thyroid nodules previously treated with laser thermal ablation were retrospectively analyzed. Histopathological evaluation focused on architectural changes, nuclear atypia, capsule alterations, degenerative phenomena, and evidence of invasion. Immunohistochemical analysis included galectin-3 (Gal-3), HBME-1, BRAF V600E, p53, and Ki-67. In addition, molecular profiling for the principal thyroid cancer-related alterations, including BRAF, RAS family genes, TERT promoter mutations, PIK3CA alterations, and RET rearrangements, was performed using targeted next-generation sequencing. All nodules showed treatment-related reactive and degenerative changes, including fibrosis\/sclerosis, subcapsular hemorrhage, focal oncocytic metaplasia, and architectural distortion. No true capsular or vascular invasion was identified. Immunohistochemically, all cases were negative for Gal-3 and BRAF V600E, while HBME-1 expression was absent or only focally weak. Ki-67 proliferative activity remained consistently low (&lt;3%) in all cases. Molecular analyses did not identify pathogenic alterations involving BRAF, RAS, TERT promoter, PIK3CA, or RET genes in any case. Thermal ablation induces reproducible reactive and degenerative histologic alterations that may closely mimic follicular or papillary thyroid neoplasms. The absence of malignancy-associated immunohistochemical and molecular alterations strongly supports the benign nature of these lesions and highlights the importance of an integrated morphologic, immunohistochemical, and molecular diagnostic approach in challenging post-ablation specimens. Thermally ablated thyroid nodules may display significant pseudo-neoplastic changes that can lead to overdiagnosis of carcinoma. Awareness of these treatment-related alterations, combined with immunohistochemical and molecular profiling, represents a reliable strategy to distinguish reactive post-ablation changes from true thyroid malignancy and to avoid inappropriate clinical management.<\/jats:p>","DOI":"10.3390\/ijms27135880","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T08:26:15Z","timestamp":1782807975000},"page":"5880","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Morphologic, Immunohistochemical, and Molecular Features of Laser-Ablated Thyroid Nodules: Diagnostic Pitfalls and Differential Diagnosis with Thyroid Carcinoma"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4957-3283","authenticated-orcid":false,"given":"Pietro","family":"Tralongo","sequence":"first","affiliation":[{"name":"Department of Biomedical, Dental and Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda","family":"Russotto","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of the Adulthood and of the Developing Age \u201cGaetano Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3478-9217","authenticated-orcid":false,"given":"Valeria","family":"Zuccal\u00e0","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of the Adulthood and of the Developing Age \u201cGaetano Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1132-1761","authenticated-orcid":false,"given":"Vincenzo","family":"Fiorentino","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of the Adulthood and of the Developing Age \u201cGaetano Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina Gloria","family":"Micali","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of the Adulthood and of the Developing Age \u201cGaetano Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariausilia","family":"Franchina","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of the Adulthood and of the Developing Age \u201cGaetano Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovica","family":"Pepe","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of the Adulthood and of the Developing Age \u201cGaetano Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8530-2474","authenticated-orcid":false,"given":"Walter","family":"Giordano","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Dental and Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1349-0910","authenticated-orcid":false,"given":"Gabriele","family":"Ricciardi","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Dental and Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5638-0508","authenticated-orcid":false,"given":"Mariagiovanna","family":"Ballato","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Dental and Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1905-8700","authenticated-orcid":false,"given":"Emanuela","family":"German\u00e0","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Dental and Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Magliolo","sequence":"additional","affiliation":[{"name":"Department of Pathology, \u201cSan Vincenzo\u201d Hospital, 98039 Taormina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serenella","family":"Ristagno","sequence":"additional","affiliation":[{"name":"Department of Oncology, Section of Endocrine Surgery, \u201cSan Vincenzo\u201d Hospital, 98039 Taormina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3819-4229","authenticated-orcid":false,"given":"Esther Diana","family":"Rossi","sequence":"additional","affiliation":[{"name":"Division of Anatomic Pathology and Histology, Catholic University of Sacred Heart, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6260-6310","authenticated-orcid":false,"given":"Maurizio","family":"Martini","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of the Adulthood and of the Developing Age \u201cGaetano Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Fadda","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of the Adulthood and of the Developing Age \u201cGaetano Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Russotto, F., Fiorentino, V., Pizzimenti, C., Micali, M.G., Franchina, M., Pepe, L., Riganati, G., Giordano, W., Magliolo, E., and Ristagno, S. (2024). Histologic Evaluation of Thyroid Nodules Treated with Thermal Ablation: An Institutional Experience. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251810182"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1089\/thy.2010.0189","article-title":"Percutaneous Laser Ablation of Cold Benign Thyroid Nodules: A 3-Year Follow-Up Study in 122 Patients","volume":"20","author":"Valcavi","year":"2010","journal-title":"Thyroid"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/thy.2015.0020","article-title":"2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer","volume":"26","author":"Haugen","year":"2016","journal-title":"Thyroid"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1080\/02656736.2019.1575482","article-title":"Minimally-invasive treatments for benign thyroid nodules: A Delphi-based consensus statement from the Italian minimally-invasive treatments of the thyroid (MITT) group","volume":"36","author":"Papini","year":"2019","journal-title":"Int. J. Hyperth."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1148\/radiol.2321021368","article-title":"Thyroid Tissue: US-guided Percutaneous Laser Thermal Ablation","volume":"232","author":"Pacella","year":"2004","journal-title":"Radiology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"576576","DOI":"10.1155\/2015\/576576","article-title":"Surgical and Pathological Changes after Radiofrequency Ablation of Thyroid Nodules","volume":"2015","author":"Dobrinja","year":"2015","journal-title":"Int. J. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1746-1596-5-9","article-title":"Utility of immunohistochemical markers in differentiating benign from malignant follicular-derived thyroid nodules","volume":"5","author":"Saleh","year":"2010","journal-title":"Diagn. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"117","DOI":"10.3803\/EnM.2019.34.2.117","article-title":"Long-Term Outcomes Following Thermal Ablation of Benign Thyroid Nodules as an Alternative to Surgery: The Importance of Controlling Regrowth","volume":"34","author":"Sim","year":"2019","journal-title":"Endocrinol. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5615","DOI":"10.1007\/s00330-023-09481-8","article-title":"Analysis and prediction of regrowth in benign thyroid nodules undergoing radiofrequency ablation: A retrospective study with a 5-year follow-up","volume":"33","author":"Li","year":"2023","journal-title":"Eur. Radiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1097\/SLA.0000000000005800","article-title":"Long-term Outcomes of Ultrasound-guided Thermal Ablation for the Treatment of Solitary Low-risk Papillary Thyroid Microcarcinoma: A Multicenter Retrospective Study","volume":"277","author":"Yan","year":"2023","journal-title":"Ann. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1007\/s00330-021-08289-8","article-title":"Image-guided thermal ablation in autonomously functioning thyroid nodules. A retrospective multicenter three-year follow-up study from the Italian Minimally Invasive Treatment of the Thyroid (MITT) Group","volume":"32","author":"Mauri","year":"2022","journal-title":"Eur. Radiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"609","DOI":"10.3348\/kjr.2018.0696","article-title":"Ethanol Ablation of the Thyroid Nodules: 2018 Consensus Statement by the Korean Society of Thyroid Radiology","volume":"20","author":"Hahn","year":"2019","journal-title":"Korean J. Radiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1159\/000516469","article-title":"Thermal ablation for benign thyroid nodules: Recommendations from the ETA-CIRSE Consensus Document","volume":"10","author":"Mauri","year":"2021","journal-title":"Eur. Thyroid J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1089\/thy.2008.0202","article-title":"Thyroid Nodules and Related Symptoms Are Stably Controlled Two Years After Radiofrequency Thermal Ablation","volume":"19","author":"Spiezia","year":"2009","journal-title":"Thyroid"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"934595","DOI":"10.1155\/2014\/934595","article-title":"Radiofrequency Ablation Compared to Surgery for the Treatment of Benign Thyroid Nodules","volume":"2014","author":"Bernardi","year":"2014","journal-title":"Int. J. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1007\/s00330-017-5039-x","article-title":"Thermal ablation of thyroid nodules: Are radiofrequency ablation, microwave ablation and high intensity focused ultrasound equally safe and effective methods?","volume":"28","author":"Korkusuz","year":"2018","journal-title":"Eur. Radiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"152479","DOI":"10.1016\/j.anndiagpath.2025.152479","article-title":"Cytomorphological changes in thyroid nodules induced by radiofrequency ablation therapy: Emphasis on recurrent papillary thyroid carcinoma","volume":"77","author":"Cho","year":"2025","journal-title":"Ann. Diagn. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1002\/lsm.20805","article-title":"Ex vivo and in vivo evaluation of laser-induced thermotherapy for nodular thyroid disease","volume":"41","author":"Ritz","year":"2009","journal-title":"Lasers Surg. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Li, S., Yu, M.-A., Zhao, Z.-L., Wei, Y., Peng, L.-L., and Li, Y. (2025). Changes in thyroid function after thermal ablation of thyroid nodules. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1557725"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S2213-8587(21)00049-8","article-title":"A worldwide journey of thyroid cancer incidence centred on tumour histology","volume":"9","author":"Rossi","year":"2021","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ozolins, A., Narbuts, Z., Strumfa, I., Volanska, G., Stepanovs, K., and Gardovskis, J. (2012). Immunohistochemical Expression of HBME-1, E-cadherin, and CD56 in the Differential Diagnosis of Thyroid Nodules. Medicina, 48.","DOI":"10.3390\/medicina48100074"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E1414","DOI":"10.1210\/jc.2013-1408","article-title":"Immunohistochemical Detection of Mutated BRAF V600E Supports the Clonal Origin of BRAF-Induced Thyroid Cancers Along the Spectrum of Disease Progression","volume":"98","author":"Ghossein","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1007\/s12022-012-9192-0","article-title":"Pathological findings of thyroid nodules after percutaneous laser ablation: A series of 22 cases with cyto-histological correlation","volume":"23","author":"Piana","year":"2012","journal-title":"Endocr. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.21037\/gs-24-221","article-title":"Microwave ablation: A technical and clinical comparison to other thermal ablation modalities to treat benign and malignant thyroid nodules","volume":"13","author":"Luo","year":"2024","journal-title":"Gland Surg."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Pizzimenti, C., Fiorentino, V., Ieni, A., Rossi, E.D., German\u00e0, E., Giovanella, L., Lentini, M., Alessi, Y., Tuccari, G., and Campenn\u00ec, A. (2023). BRAF-AXL-PD-L1 Signaling Axis as a Possible Biological Marker for RAI Treatment in the Thyroid Cancer ATA Intermediate Risk Category. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241210024"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s12020-019-02019-3","article-title":"Efficacy of thermal ablation in benign non-functioning solid thyroid nodule: A systematic review and meta-analysis","volume":"67","author":"Trimboli","year":"2020","journal-title":"Endocrine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1007\/s12020-019-02089-3","article-title":"Thermal ablation procedures: The need of careful appraisal","volume":"67","author":"Pacella","year":"2020","journal-title":"Endocrine"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"846584","DOI":"10.1155\/2013\/846584","article-title":"P53 and Expression of Immunological Markers May Identify Early Stage Thyroid Tumors","volume":"2013","author":"Marcello","year":"2013","journal-title":"Clin. Dev. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e230067","DOI":"10.1530\/ETJ-23-0067","article-title":"2023 European Thyroid Association Clinical Practice Guidelines for thyroid nodule management","volume":"12","author":"Durante","year":"2023","journal-title":"Eur. Thyroid J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1177\/10507256251363120","article-title":"2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer","volume":"35","author":"Ringel","year":"2025","journal-title":"Thyroid"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5880\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:12:25Z","timestamp":1783419145000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5880"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":30,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135880"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135880","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]}}}